The chemical entity (2S)-2-[(1S)-1-carbethoxybutylamino]-1-oxopropyl-(2S,3aS,7aS)-perhydroindole-2-carboxylic acid of formula (II), known generically as perindopril and its pharmaceutically acceptable salts, specially salt of perindopril with tertiary butyl amine i.e. perindopril erbumine are commercially valuable ACE Inhibitors, useful for the treatment of hypertension.
Vincent et. al. in U.S. Pat. No. 4,508,729 disclose a method for preparation of perindopril monoammonium salt, as a mixture of two diastereomers, involving reductive amination of (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole with pyruvic acid in the presence of sodium cyanoborohydride. The (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole, in turn is prepared by reaction of (2S)-2-ethoxycarbonylperhydroindole with L-BOC.-alanine to give (2S)-N-[(S)-BOC.-alanyl]-2-ethoxycarbonylperhydroindole, which on step-wise removal of the carboxyl and amino protecting groups gives (2S)-1-[(S)-alanyl]-2-carboxyperhydroindo. The synthesis is schematically represented hereinbelow.

However, this method gives perindopril as a mixture of diastereomers and there are no enabling disclosure in the patent as to how the diastereomers are separated to give perindopril or its tert-butylamine salt i.e. perindopril erbumine having the desired (S) configuration for all the five chiral centers in the molecule. Moreover, the method involves protection of the amino group of the alanine moiety as the t-BOC group, which necessitates use of corrosive trifluoroacetic acid for its subsequent removal.
Vincent et. al. in U.S. Pat. No. 4,902,817 disclose a stereoselective process for the industrial synthesis of N-[(S)-1-carbethoxybutyl]-(S)-alanine comprising reaction of ethyl-L-norvalinate hydrochloride with pyruvic acid under catalytic hydrogenation conditions. The N-[(S)-1-carbethoxybutyl]-(S)-alanine thus obtained is a key intermediate for perindopril. The synthesis is schematically represented hereinbelow.

Vincent et. al. in U.S. Pat. No. 4,914,214 disclose an industrial method for synthesis of perindopril erbumine comprising reacting ethyl or benzyl ester of (2S, 3aS,7aS)-2-carboxyperhydroindole with (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine in an alkaline medium in the presence of a catalyst, such as dicyclohexylcarbodiimide in the presence of 1-hydroxybenzotriazole to give perindopril ethyl or benzyl ester. Subsequent deprotection and salt formation with tert-butyl amine gives perindopril erbumine.

Similar chemistry as disclosed in U.S. Pat. No. 4,914,214 is also embodied in Vincent et. al's. EP Patent No. 0 129 461.
Vincent et. al. in EP Patent No. 0 309 324 disclose yet another method for synthesis of (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reaction of L-alanine benzyl ester p-toluenesulfonate with ammonia to form the free base, which is condensed with ethyl α-bromo valerate to give a racemic mixture of N-[(S)-1-carbethoxybutyl]-(S)-alanine and N-[(R)-1-carbethoxybutyl]-(S)-alanine. The (S) isomer is separated by resolution with maleic acid and subsequent removal of the benzyl ester group provides the (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, which can be further elaborated to perindopril and perindopril erbumine.

Meizei et. al. in EP Patent No. 1 256 590 disclose a process for preparation of (2S, 3aS, 7aS)-1-(S)-alanyl-octahydro-1H-indole-2-carboxylic acid as an intermediate for perindopril comprising reaction of (2S)-2,3-dihydroindole-2-carboxylic acid with t-BOC-L-alanine to form the amide compound followed by hydrogenation to give (2S, 3aS, 7aS)-1-(S)-alanyl-octahydro-1H-indole-2-carboxylic acid, which can be further elaborated to perindopril.

Souvie et. al. in published PCT Appln. No. WO 01/56353 disclose a method for preparation of the (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reacting sodium pyruvate with L-norvalinate ester under reducing conditions using palladium carbon as catalyst.

Souvie et. al. in published PCT Appln. No. WO 01/56972 disclose yet another method for preparation of the (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reacting 1-alanine and ethyl 2-oxo-pentanoic acid under catalytic hydrogenation conditions and isolating the product at a pH between 3 to 3.5, followed by crystallization.

Langlois et. al. in published PCT Appln. No. WO 01/58868 disclose a further method for preparation of the (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reacting benzyl ester of (2S, 3aS,7aS)-2-carboxyperhydroindole, p-toluenesulfonate salt with (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine in the presence of 0.4 to 0.6 moles of 1-hydroxybenzotriazole; 1 to 1.2 moles of dicyclohexylcarbodiimide and I mole of triethylamine at 77° C. to give the dipeptide compound, which on debenzylation gives perindopril.

Serra et. al. in published PCT Appln. No. WO 96/33984 disclose N-sulfoxy anhydrides of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl/butyl-S-alanine, and a process for preparation of several ACE inhibitors including perindopril using the said N-sulfoxy anhydride compounds. The N-sulfoxy anhydride is in turn prepared by reacting the corresponding carboxylic acid compound with N-(chlorosulfinyl)-heterocyclic compound, wherein the heterocycle is an alkyl imidazole, benzimidazole, tetrazole or other similar heterocyclic compounds.

Cid et. al. in EP Patent No. 1 279 665 disclose N-carboxy anhydride of N-[1-(S)-ethoxycarbonyl-3-butyl-S-alanine, and a process for preparation of perindopril using the said N-carboxy anhydride compound.

However, this method utilizes toxic and hazardous phosgene for preparation of the N-carboxy anhydride compound, thereby rendering it unsuitable for commercial manufacture.
Suh et. al. in GB Patent No. 2 095 252 claim certain N-(substituted aminoalkanoyl) heterocyclic compounds having antihypertensive and ACE Inhibition activity and a process for preparation thereof, which comprises an amide forming reaction of a suitable amine compound and the reactive derivatives of the suitable carboxylic acid compound. The reactive carboxylic derivatives mentioned therein include acyl halides, anhydrides, mixed anhydrides, lower alkyl esters, carbodiimides, carbonyl diimidazoles and the like.

However, this patent disclosure does not include perindopril as the antihypertensive and ACE Inhibitory compounds mentioned therein.
Palomo et. al. in DE Patent No: 197 21 290 describe a method for preparation of several ACE Inhibitors of formula (D), including perindopril, wherein Z is alkyl or phenyl and R1 is an amino acid as found in commercially valuable ACE inhibitors. The process comprises the steps of first silylating the compound of formula (A) to give the (bis)silyl derivative of formula (B), followed by reaction of compound (B) with thionyl chloride to give the silylated acid chloride derivative of formula (C). Compound (C) is then reacted with the respective amino acid, R1H to give compound of formula (D).

This method is however, lengthy and not cost-effective since there is a step of silylation using expensive silylating agents and subsequent step of desilylation involved.
It would be apparent from the above that while there are several known methods available for synthesis of perindopril, however, most of the methods either involve utilization of hazardous or costly coupling agents like dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, toxic chemicals like phosgene or essentially require special acidic or alkaline conditions. These in turn lead to complexities in manufacture and render the methods to obtain such product less cost-effective.